Phase 1/2 Trial of Carfilzomib Plus High-Dose Melphalan Preparative Regimen for Salvage Autologous Hematopoietic Cell Transplantation Followed by Maintenance Carfilzomib in Patients with Relapsed/Refractory Multiple Myeloma

We performed a phase 1/2 trial to investigate the safety and activity of the second-generation proteasome inhibitor Carfilzomib (K) on days -3/-2 in combination with melphalan 200?mg/m² (MEL200) on day -2 (K-MEL) in patients with relapsed multiple myeloma (MM) undergoing autologous hematopoietic cell transplantation (phases 1 and 2). Patients without progression received 12 cycles of K maintenance at 36?mg/m² days 1, 8, and 15 (schedule A) or days 1, 2, 15, and 16 (schedule B), with patients being treated for 2 cycles in each schedule and on the patient-preferred schedule for the remaining cycles (phase 2). The patients had received a median of 3 previous lines of therapy, 56% had undergone previous AHCT, and 51% had received previous K therapy. During phase 1 (n?=?15), the maximum tolerated dose of K in combination with MEL200 was not reached, so the maximum tested dose of 27?mg/m² (on day -3) and 56 mg/m² (on day -2) was used in phase 2. The rate of?very good partial response after K-MEL therapy (n?=?44) was 59.2%, compared with 13.7% before K-MEL therapy. Among patients starting maintenance therapy (n?=?27), 12-month progression-free survival was 66.7% and 12-month overall survival was 88.1%. There was no strong patient preference for either schedule. Two patients discontinued maintenance due to toxicity. K-MEL followed by K maintenance is safe and active salvage therapy in patients with MM.     

Isolated hypoxic hepatic perfusion with melphalan in patients with irresectable ocular melanoma metastases

Aim

Ocular melanoma prefers to metastasize to the liver and the liver is the sole site of metastatic disease in 80% of patients. Until now there has been no standard treatment available and these patients have a very poor prognosis (median survival 2–5 months). Isolated hepatic perfusion may be an option in patients with irresectable hepatic ocular melanoma metastases. The aim of this study was to evaluate applicability, toxicity and response in this selected group of ocular melanoma patients by treatment with isolated hypoxic hepatic perfusion with retrograde outflow (IHHP) with melphalan.

Methods

From September 2002 until July 2006 eight consecutive patients were included in this study. IHHP was performed with inflow via the hepatic artery and retrograde outflow via the portal vein during 25 min with 1 mg/kg melphalan. The perfusion was followed by a complete wash-out procedure.

Results

The median total operation time was 4 h with a median blood/fluid loss of 1100 ml. No postoperative mortality was observed. Median hospital stay was 9.5 days. Toxicity was moderate: WHO grade 3 leukocytopenia in 3 patients, grade 3 hepatic toxicity in 1 patient. In 37% of patients (3/8) a partial response could be demonstrated 3 months after IHHP. Stable disease was found in 3 patients and progressive disease in 2 patients. Median time to local progression was 6 months and the median survival was 11 months.

Conclusion

Melphalan-based IHHP with retrograde outflow is a safe treatment option for patients with irresectable ocular melanoma metastases. Survival benefit seems to be comparable to classical IHHP.     

Intravitreal chemotherapy for vitreous seeding in retinoblastoma: Recent advances and perspectives

For decades intravitreal chemotherapy (IViC) remained virtually banished from the therapeutic armamentarium against retinoblastoma, except as a heroic attempt of salvage before enucleation in only eyes with refractory vitreous seeding. Very recently, we have initiated a reappraisal of this route of administration by (1) profiling eligibility criteria, (2) describing a safety-enhanced injection procedure, (3) adjusting the tumoricidal dose of melphalan, and (4) reporting an unprecedented efficacy in terms of tumor control of vitreous seeding. Since then, intravitreal chemotherapy is being progressively implemented worldwide with great success, but still awaits formal validation by the ongoing prospective phase II clinical trial. As far as preliminary results are concerned, IViC appears to achieve complete vitreous response in 100% of the 35 newly recruited patients irrespective of the previous treatment regimen, including external beam radiotherapy and/or intra-arterial melphalan. In other words, vitreous seeding, still considered as the major cause of primary and secondary enucleation, can now be controlled by IViC. However, sterilization of vitreous seeding does not necessarily translate into eye survival, unless the retinal source of the seeds receives concomitant therapy. In conclusion, IViC, an unsophisticated and cost-effective treatment, is about to revolutionize the eye survival prognosis of vitreous disease in advanced retinoblastoma.     

Vasculopatía coroidea oclusiva tras quimioterapia intraarterial: hallazgos en la RMN

PurposeTo evaluate magnetic resonance imaging (MRI) findings in patients suffering choroidal occlusive vasculopathy (COV) after intra-arterial chemotherapy (IAC) for retinoblastoma.MethodsA retrospective study of 37 eyes of 34 patients receiving IAQ between 2016 to 2021 as primary or secondary treatment for retinoblastoma was conducted. Twenty-two patients received systemic chemotherapy with carboplatin, vincristine and etoposide. The rest received IAC as primary treatment. The drugs administered were melphalan (3-4 mg), carboplatin (40 mg) plus topotecan (20 mg). The patients were examined under general anaesthesia every month to observe tumor regression and possible complications of the treatment. For the patients with COV an MRI was obtained to analyse the choroidal thickness and axial ocular length.ResultsA COV was observed in 5 of the 37 eyes receiving IAC (13,51%), all of them with a complete sectorial choroidopathy not sparing the fovea (grade 2). In 4 of the 5 patients the choroidal thickness was decreased and in three cases the size of the eye which presented COV was clearly smaller than the contralateral eye. Tumor control was archived in all 5 patients.ConclusionIn our cases COV was associated with reduction of thinning of choroid and eye length in the MRI. A new classification maybe needed to correlate better with the severity of the complication affecting the fovea. Although early results generally are favorable to the use of IAC, longer follow up and scrupulous documentation of side effects will be necessary to know the true role of IAC for retinoblastoma.     

Treatment of patients with advanced cardiac AL amyloidosis with oral melphalan, dexamethasone, and thalidomide

Patients with primary (AL) amyloidosis and heart failure have a very poor prognosis and cannot tolerate aggressive therapy, such as autologous stem cell transplantation and high-dose dexamethasone-based regimens. We prospectively treated 22 patients with advanced cardiac amyloidosis combining oral melphalan, thalidomide, and reduced intensity dexamethasone (MTD). Six patients died due to cardiac amyloidosis before completing cycle 3. Early death was associated with reduced ejection fraction. Eight patients achieved a hematological response and four achieved a durable improvement of cardiac dysfunction. Treatment with MTD is feasible in patients with advanced cardiac AL amyloidosis and effective in subjects with preserved systolic function. G.P. was partly supported by an investigator fellowship from Collegio Ghislieri, Pavia, Italy. Study supported in part by the Euramy Research Project funded by the European Community Sixth Framework Program     

伏立诺他与左旋苯丙氨酸氮芥对人类多发性骨髓瘤细胞的协同作用

 目的　观察体外伏立诺他和左旋苯丙氨酸氮芥联合对人类多发性骨髓瘤细胞株U266、KM3的抗瘤作用。方法　应用MTT法分别测定伏立诺他和左旋苯丙氨酸氮芥不同浓度对骨髓瘤细胞株U266、KM3的抗瘤作用,计算两药的IC50值;应用MTT法测定固定一种药物浓度联合不同浓度另一药物时对U266、KM3的抑制作用,计算药物联合指数（CI）,判断药物相互作用。 结果　伏立诺他单药对U266细胞的IC50值介于5.0～7.5 μmol／L,对KM 3细胞的IC50值介于2.5～5.0 μmol／L;左旋苯丙氨酸氮芥单药杀伤U266细胞的IC50值介于40～60 μmol／L,杀伤KM3细胞的IC50值介于60～80 μmol／L。固定伏立诺他浓度（U266细胞中为1.25 μmol／L,KM 3细胞中浓度为1.0 μmol／L）,在U266细胞中左旋苯丙氨酸氮芥浓度为20、40、60、80 μmol／L时均CI＜0.9,表现为协同作用,在KM3细胞中左旋苯丙氨酸氮芥浓度为40、60、80、100 μmol／L时均CI＜0.9,表现为协同作用;固定左旋苯丙氨酸氮芥浓度（U266细胞中为10 μmol／L,KM3细胞中浓度为20 μmol／L）,在U266细胞中伏立诺他浓度为2.5、5.0、7.5 μmol／L时均CI＜0.9,表现为协同作用,在KM3细胞中伏立诺他浓度为1.0、2.5、5.0 μmol／L时均CI＜0.9,表现为协同作用;当伏立诺他浓度为7.5 μmol／L联合左旋苯丙氨酸氮芥20 μmol／L时呈现相加作用（CI＝0.93）。结论　体外伏立诺他单药对两种多发性骨髓瘤细胞株有明显的杀伤作用,与左旋苯丙氨酸氮芥有协同抗骨髓瘤细胞作用。     

Isolated Limb Perfusion with Tumor Necrosis Factor Alpha and Melphalan for Locally Advanced Soft Tissue Sarcoma: Three Time Periods at Risk for Amputation

Background The aim of this study was to investigate the long-term limb salvage rate and overall survival after isolated limb perfusion (ILP) with tumor necrosis factor alpha and melphalan for locally advanced soft tissue sarcoma (STS). Methods From 1991 to 2003, 73 patients (36 men, 37 women, median age 54 [range 14–80] years) with biopsy-proven STS underwent 77 perfusions followed by delayed surgical resection, with or without adjuvant radiation. Limb salvage and overall survival curves were calculated by the Kaplan-Meier method. Results A total of 21 amputations (28%) were performed. Overall 1, 5, and 10 years’ limb salvage was 80.1% ± 4.8%, 68.2% ± 6.5%, and 60.6% ± 9.2%, respectively. We found that the risk of amputation was linked to three time periods. The first was within a year after perfusion, mainly as a result of massive necrosis of the tumor and overlying skin, resulting in soft tissue deficit or recurrent disease (n = 17). The second was within 5 years, with two amputations performed for late local recurrence. The third occurred 10 years after perfusion, with two amputations performed for critical leg ischemia. Another two patients developed a pathological fracture of the femur due to radiation osteonecrosis. These four patients received adjuvant radiotherapy. Overall, 1, 5, and 10 years’ survival was 82.9% ± 9.2%, 58.7% ± 13.1%, and 42.5% ± 18.2%, respectively. Conclusions ILP treatment with tumor necrosis factor alpha and melphalan followed by delayed surgical resection and adjuvant radiation treatment is an effective limb salvage treatment regimen for locally advanced STS. However, we observed late morbidity, with two amputations performed for critical leg ischemia and two pathological fractures of the femur in patients receiving adjuvant radiotherapy.     

Evaluation of the efficacy and toxicity of upper extremity isolated limb infusion chemotherapy for melanoma: An Australian multi-center study

BackgroundIsolated limb infusion (ILI) is a minimally invasive treatment for patients with locally advanced extremity melanoma. Most studies combine results of upper-limb ILI (UL-ILI) and lower-limb ILI (LL-ILI), leaving UL-ILIs relatively underreported as LL-ILIs comprise the vast majority in these reports. However, differences between the two procedures may be clinically important. The aim of this study was to evaluate the efficacy and toxicity of UL-ILI in an Australian multi-center setting.Patients and methods316 ILI procedures for melanoma performed between 1992 and 2008 in five Australian institutions were analyzed. In all institutions melphalan (±actinomycin D) was circulated in the isolated limb for 20–30 min.ResultsBaseline patient characteristics for UL-ILI (n = 27) and LL-ILI (n = 289) were similar, except that more men underwent UL-ILI (66% vs. 38%; p = 0.007) and disease in LL-ILI was mostly located on the distal limb (p = 0.02). Median tourniquet times were shorter for UL-ILI (38 vs. 48 min; p = 0.04) and UL-ILI patients experienced less limb toxicity (Grade III/IV in 24% vs. 31%; p = 0.01). Complete response (CR) rates were similar: 33% after LL-ILI (p = 0.70), 30% after UL-ILI, while overall response (OR) rates were higher after LL-ILI: (76%) than UL-ILI (59%; p = 0.05). No difference in survival was seen.ConclusionsUL-ILI is safe to perform and effective, resulting in low limb toxicity. CR rates were similar to those for LL-ILI, but OR rates were lower for UL-ILI. It may be possible to improve OR rates achieved by UL-ILI by optimizing perioperative factors, while maintaining low toxicity.     

Longitudinal Real-World Neuropathy and Patient-Reported Outcomes With Bortezomib and Lenalidomide in Newly Diagnosed Multiple Myeloma

BackgroundPeripheral neuropathy is a common treatment-emergent side effect during the treatment of newly diagnosed multiple myeloma. Although bortezomib is most commonly implicated, real-world data suggest that lenalidomide and dexamethasone (VRd) and autologous stem cell transplantation (ASCT) may also contribute to neuropathy and health-related quality of life (HRQoL).MethodsThe Multiple Myeloma Research Foundation (MMRF) CoMMpass Registry was queried for all patients who received frontline VRd or bortezomib, cyclophosphamide and dexamethasone (VCd). Incidence of neuropathy and patient-reported HRQoL outcomes over the first 12 months after diagnosis were compared between patients receiving VRd or VCd with or without early ASCT before 6 months.ResultsThere were 368 and 191 patients treated with VRd and VCd, respectively. VRd with early ASCT was associated with worse grade 1 neuropathy compared to VRd without early ASCT, as well as compared to VCd with early ASCT. There were no differences in neuropathy between VRd and VCd without early ASCT, and no differences in grade ≥2 neuropathy. There were significant improvements in HRQoL between baseline and 12 months in both VRd and VCd cohorts, regardless of early ASCT. Development of neuropathy was not associated with decrements in progression-free survival or overall survival.ConclusionsIn this longitudinal database analysis, there were no differences in grade ≥2 neuropathy between VRd and VCd frontline induction, and overall HRQoL significantly improved across all cohorts. However, differences in grade 1 neuropathy between VRd and VCd induction suggest that lenalidomide and high-dose melphalan may augment the risk of neuropathy in newly diagnosed multiple myeloma.     

Safety and efficacy of bortezomib and melphalan combination in patients with relapsed or refractory multiple myeloma: updated results of a phase 1/2 study after longer follow-up

Bortezomib synergizes with melphalan in preclinical and early clinical studies. Updated data from our phase 1/2 study assessing the safety and efficacy of bortezomib plus melphalan in relapsed/refractory multiple myeloma (MM) are presented. Bortezomib (0.7, 1.0, or 1.3 mg/m(2)) on days 1, 4, 8, and 11 and oral melphalan (0.025-0.25 mg/kg) on days 1-4 of a 28-day cycle were administered. Hematologic toxicities defined the maximum tolerated dose as bortezomib 1.0 mg/m(2) and melphalan 0.10 mg/kg. Because dose-limiting toxicities were attributed to the more myelosuppressive melphalan, cohorts 9 and 10 with higher bortezomib (1.3 mg/m(2)) and lower melphalan (0.025 and 0.10 mg/kg) doses were added. Responses occurred in 32/46 (70%) evaluable patients: two complete (4%), five near-complete (11%), 16 partial (35%), and nine minimal (20%). Complete and near-complete responses were observed only with higher bortezomib doses. Response rates were similar in patients with prior melphalan or bortezomib. Median progression-free survival was 9 months (range, 1-24), and overall survival was 32 months (range, 1-54). The most common grade 3/4 hematologic adverse events (AEs) were neutropenia (31%/0%), thrombocytopenia (25%/2%), and anemia (13%/0%). Grade 4 tumor lysis syndrome was reported in one patient. Fewer grade 3/4 hematologic AEs were reported in cohorts 9 and 10 than in cohorts receiving lower bortezomib and higher melphalan doses. In conclusion, bortezomib plus melphalan is a steroid- and immunomodulatory drug-free regimen that may provide a treatment alternative for elderly patients and patients with significant comorbidity.